The decarboxylation of ornithine to putrescine, a reaction catalyzed by the enzyme ornithine decarboxylase (OCD), is the first step in the biosynthesis of the polyamines known as spermidine and spermine. Spermidine is formed by the transfer of an activated aminopropyl moiety from S-adenosyl S-methyl homocysteamine to putrescine, while spermine is formed by the transfer of a second aminopropyl group to spermidine. S-Adenosyl S-methyl homocysteamine is formed by the decarboxylation of S-adenosylmethionine (SAM), a reaction catalyzed by the enzyme S-adenosylmethionine decarboxylase (SAM-DC).
The polyamines, which are found in animal tissues and microorganisms, are known to play an important role in cell growth and proliferation. The onset of cell growth and proliferation is associated with both a marked increase in ODC activity and an increase in the levels of putrescine and the polyamines. Although the exact mechanism of the role of the polyamines in cell growth and proliferation is not known, it appears that the polyamines may facilitate macromolecular processes such as DNA, RNA, or protein synthesis. Polyamine levels are known to be high in embryonic tissue; in the testes, ventral prostrate, and thymus; in tumor tissue; in psoriatic skin lesions; and in other cells undergoing rapid growth or proliferation.
Since putrescine is the precursor of both spermidine and spermine, blockade of the conversion of ornithine to putrescine, such as by inhibition of ODC, should prevent new biosynthesis of these polyamines and, thus, provide beneficial physiological effects.
Much of the medical investigation which has been directed to the elucidation of the mechanism of hair growth has focused on the role of the endocrine system. As a result of such investigations, it is generally agreed that the fine, light-colored vellus hair, which covers most of the body during childhood, comes under the influence of growth hormone and of androgens to eventually become the coarser and darker terminal hairs which characterize many areas of the adult body. The desire to discover methods for controlling androgen-dependent conditions has generated a large number of studies dealing with androgen metabolism in skin. These studies have suggested that it is possible to reduce the amount of androgen capable of entering into the hair growth cycle by two means.
Firstly, the conversion of serum testosterone to dihydrotestosterone can be prevented by the inhibition of the enzyme steroid 5-alpha-reductase. Secondly, certain compounds can compete with the testosterone or dihydrotestosterone for the cytoplasmic receptor sites. The action of both types of antiandrogen compounds in skin can also affect the course of male-pattern hair growth in females, thus leading to their application in the treatment of female hirsutism. Such application is described, inter alia, in the following patents:
U.S. Pat. Nos. 4,139,638 and 4,151,540 describe the use of certain 4'-substituted and 3', 4'-disubstituted anilides for the treatment of androgen-dependent disease states such as female hirsutism and acne.
U.S. Pat. No. 4,191,775 discloses that certain 3,4-disubstituted-branched-chain-fluorinated-acylanilides may be used in the topical treatment of androgen-dependent disease conditions such as acne, female hirsutism, and seborrhoea.
U.S. Pat. No. 4,344,943 describes the topical use of certain androgenic 17-alpha-substituted steroids exemplified by 17-beta-hydroxyl-1-alpha-methyl-17-alpha-(1-methyl-2-propenyl)-5-alpha-and rostan-3-one for the treatment of diseases such as acne, seborrhoea, alopecia and female hirsutism.
West German OLS No. 2,840,144 describes the use of combinations of progesterone with either cyproterone acetate or chlormadinone acetate in the topical treatment of androgen-induced hormonal disturbances such as alopecia, female hirsutism, and acne.
The patent art also discloses a number of non-steroidal methods of reducing the growth of human hair as opposed to its conventional removal by cutting, shaving, or depilation. One such method is described in U.S. Pat. No. 3,426,137, which pertains to a process for inhibiting the growth of hair by the topical application to a depilated skin area of a composition containing a substituted benzophenone such as 2-amino-5-chlorobenzophenone. Examples in the patent illustrate the reduction of hair growth on the back area of rabbits and on the arm of a male human subject.
Another process for extending the duration of depilation is described in U.S. Pat. No. 4,370,315. The process therein comprises the topical application of a composition containing a lipoxygenase along with linoleic acid or derivative thereof. The patent describes the application of such composition to various body parts of female subjects in the majority of which regrowth of hair was clearly perceptible only after six or more weeks.
Ornithine decarboxylase was essentially unknown until the late 1960's. This enzyme remained in a state of relative obscurity until it was realized that its activity is the rate-determining step in the biosynthesis of polyamines which are produced by mammalian species. The application of this discovery has led to the administration of ODC inhibitors in the treatment of a variety of conditions. Prior art references describing such applications include, inter alia:
U.S. Pat. No. 4,413,141 relating to 2-difluoromethyl(-2,5-diaminopentanoic) acid or its salts as contra-gestational agents, for use in the treatment of benign prostatic hypertrophy, for use in slowing neoplastic cell proliferation and as an anti-protozoal agent.
U.S. Pat. No. 4,421,768 dealing with fluorinated diamino-heptene and -heptyne derivatives for use in controlling the growth rate of rapidly proliferating tumor tissue and for controlling the growth of pathogenic parasitic protozoa.
U.S. Pat. No. 4,207,315 claiming a process for treating non-malignant proliferative skin disease by the application of diamines of aliphatic hydrocarbons or derivatives of ornithine in association with a pharmaceutical carrier.
U.S. Pat. No. 4,201,788 claiming a process for treating nonmalignant proliferative skin diseases by the administration of a compound exemplified by methyl glyoxal bis-(guanyl hydrazone) in association with a pharmaceutical carrier.